The Pathophysiology and Impact of Inflammation in Nonscarred Renal Interstitium: The Banff i Lesion

Abstract

Background. Interstitial inflammation (i-INT) is the driver of T-cell–mediated rejection. Its causes, pathophysiology, kinetics, and outcomes are poorly documented. Methods. The role of i-INT was evaluated in 2055 biopsies from 775 renal transplant recipients. Results. i-INT was present in 374 (18.2% prevalence) from acute and subclinical rejection (67.4%); interstitial fibrosis and tubular atrophy (14.4%); BK virus nephropathy (BKVAN) 9.9%; and acute tubular necrosis (ATN with i-INT) in 5.9% of cases. i-INT was predicted by prior T-cell–mediated rejection and BKVAN, human leukocyte antigen mismatch, cyclosporine therapy, and indication biopsy for dysfunction. It correlated with tubulitis, arteritis, and antibody markers within concurrent histology (P < 0.001). After treatment, renal functional recovery was best with histological ATN, milder i-INT, and early posttransplant biopsy times. The initial histological improvement of inflammation depended on baseline i-INT severity. Complete resolution to Banff i0 was predicted by early biopsy time, antilymphocyte therapy, recipient age, and medication compliance (all P < 0.001). Clearance i-INT was followed by delayed resolution of tubulitis (P < 0.001). i-INT was associated with histological ATN, renal dysfunction, and increased incident fibrosis on sequential pathology. Progressive fibrosis following related-rejection i-INT was dependent on tubulitis using multivariable analysis. In contrast, fibrogenesis after BKVAN or ATN was unrelated to inflammation. i-INT cases were followed by recurrent rejection in 35.3%, increased graft loss, and greater patient mortality. Multiple complementary outcome analyses determined the optimal lower diagnostic threshold for inflammation was Banff i1 score. Conclusions. i-INT is a heterogeneous pathological phenotype that results in adverse functional and structural outcomes, for which active and robust therapy should be considered.

The Pathological and Clinical Diversity of Acute Vascular Rejection in Kidney Transplantation

“…We defined isolated VR as arteritis without interstitial inflammation with tubulitis (Banff i < 1/t < 1), which was compared with inflamed VR (including “borderline” TCMR, i ≥ 1/t ≥ 1 irrespective of C4d and DSA). 18,19…”

Pure T-cell Mediated Rejection Following Kidney Transplant According to Response to Treatment&nbsp;

“…Molecular assessment using a microarray of biopsies in KT is a feasible and accurate method for complementing histologic diagnosis 16 . Discrepancies between molecular and histological diagnosis in TCMR mainly develop in in ammatory conditions due to acute kidney injury, ambiguous isolated vlesions, scarred tissues, and combined polyomavirus related lesions 13,19 . ABMR may induce tubulointerstitial in ammation and thus mimic TCMR-however, this may be missed by the site-speci c nature of histologic diagnosis 20,21 .…”

“…Nankivell et al showed that interstitial in ammation by mononuclear cells is the initial event of cellular rejection that results in adverse histological and functional outcomes, and is thus a key diagnostic feature of TCMR. However, the t-score replaced i score as a signi cant predictor of progressive brosis 19 . Although Sellares et al suggested that both i and t scores had no associations with long-term GS, another study showed that intimal arteritis (v) and t score were independent indicators of GS, which is similar to our study 24,25 .…”

Pure T-cell mediated rejection following kidney transplant according to response to treatment

“…Molecular assessment using a microarray of biopsies in KT is a feasible and accurate method for complementing histologic diagnosis [16]. Discrepancies between molecular and histological diagnosis in TCMR mainly develop in inflammatory conditions due to acute kidney injury, ambiguous isolated v-lesions, scarred tissues, and combined polyomavirus related lesions [13,21]. The recent study also demonstrated that MMDx scores had a good correlation with histology.…”

“…Nankivell et al showed that interstitial inflammation by mononuclear cells is the initial event of cellular rejection that results in adverse histological and functional outcomes, and is thus a key diagnostic feature of TCMR. However, the t-score replaced i score as a significant predictor of progressive fibrosis [21]. Although Sellares et al…”